Pellet formulation for the treatment of the intestinal tract

ABSTRACT

An orally adminsterable pharmaceutical pellet formulation for the treatment of the intestinal tract is disclosed, which comprises a core and an enteric coating, the core including, as a pharmaceutical active compound, aminosalicylic acid or a pharmaceutically tolerable salt or a derivative thereof.

RELATED APPLICATIONS

[0001] This application is a Divisional of U.S. patent application Ser.No. 09/906,494, filed Jul. 16, 2001, which is a Continuation of Ser. No.09/194,213, filed on Aug. 30, 1999, which was a filing under 35 U.S.C.371 PCT/EP98/02319, filed on Apr. 20, 1998, which claimed priority fromGerman Application No. 197 32 903.9, filed Jul. 30, 1997, whichapplications are incorporated by reference and made a part hereof.

FIELD OF THE INVENTION

[0002] The present invention relates to a pellet formulation for thetreatment of the intestinal tract, which comprises, as a pharmaceuticalactive compound, aminosalicylic acid or a pharmaceutically tolerablesalt or derivatives thereof.

BACKGROUND OF THE INVENTION

[0003] The active compound aminosalicylic acid (in particular 5-ASA) orits derivatives have been used successfully for a relatively long timefor the treatment of intestinal disorders, such as, for example,ulcerative colitis and Crohn's disease (DE 31 51 196 A1).

[0004] The use of 5-ASA and its derivatives as a chemotherapeutic agentin colonic cancer is likewise known, polyps in the colon and rectumbeing associated with an increased risk of carcinoma (WO 95/18622).

[0005] A coloscopic polypectomy in patients with polyps in the colonand/or rectum results in a considerable reduction in risk of theformation of colonic carcinomas and is recommended as a therapy, inparticular in the case of colorectal polyps. The reccurrence rate afterpolypectomy, however, is high and amounts to about 6-30% per year.Aminosalicylic acid is suitable for the longer-term treatment of suchpatients and lowers the reccurrence rate of colorectal polyps.

[0006] The action of aminosalicylic acid in the treatment of intestinaldisorders, or in the prevention of their recurrence or in the preventionof secondary disorders arising therefrom and possible accompanyingdisorders takes place by means of the contact of the active compounddirectly at the site of the disorder in the intestine, the action of theaminosalicylic acid, or a derivative thereof, being directly related toits local concentration in the intestinal area to be treated.

[0007] Since inflammatory processes often affect relatively largesections of the intestinal tract, the pharmaceutical form should spreadreproducibly over wide areas of the intestine and release the activecompound only at the site of inflammation.

[0008] A problem in the treatment with aminosalicylic acid is that theactive compound is very easily absorbed and can be excreted via thekidney before its action can occur.

[0009] In the prior art, tablets and pellets are known which are coatedwith an enteric coating in order to thus prevent a premature release ofthe active compounds.

[0010] FR-A2 692 484 discloses a tablet for the controlled release of4-ASA in a hydrophilic matrix which consists of swellable polymersforming a gel barrier, and having an enteric coating. After dissolutionof the coating, the matrix swells and forms a gel barrier through whichthe active compound diffuses out. After an approximately two-hour lagphase, the composition disclosed in FR-A 2 692 484 releases the activecompound approximately linearly in the intestine over a period of timeof a further 14 h.

[0011] EP 0 453 001 A1 discloses a pharmaceutical composition in whichthe active compound is covered with at least two membranes, of which oneis soluble at a pH of ≧5.5 and the other is insoluble at this pH but ispermeable to the intestinal fluids.

[0012] EP 0 148 811 A1 discloses a pharmaceutical composition whichconsists of a core which contains the active compound. The core issurrounded by two layers, of which the inner layer is a diffusionmembrane and the second layer is an anionic polymer and/or a fatty acidhaving a pK_(a) of 4.5 to 7.

[0013] EP 0 629 398 A1 discloses pharmaceutical compositions in whichthe active compound-containing core is surrounded by an enteric phase.According to Example 2, the core can contain small amounts ofhydroxypropylcellulose. The active compound should be released rapidlyafter dissolution of the enteric phase.

[0014] EP 0 485 840 A2 discloses an oral pharmaceutical form whichcontains a shell material surrounding the active compound consisting ofa polysaccharide and a film-forming polymer material.

[0015] A disadvantage in the case of the pharmaceutical formulationsknown in the prior art is that the active compound is also absorbed intothe blood circulation. This amount of active compound is thus lacking inthe intestine, so that the effective dose of the medicament is reducedby the part of the active compound which is found in the blood.

[0016] Moreover, patients who suffer from intestinal disordersfrequently have to be further treated over relatively long periods withthe active compound, or derivatives thereof, after the acute disorderhas died down in order to prevent the disorder flaring up again orsecondary disorders resulting from the original disorder. In the case ofsuch a long-term treatment, however, it has proven to be a problem thata certain nephrotoxicity of systemically available 5-ASA, i.e. 5-ASAfound in the bloodstream, or derivatives thereof cannot be excluded (M.Barry, Prescribers Journal, 1992, 32, 205).

[0017] It is thus an object of the present invention to make availablean orally administrable pharmaceutical formulation which does not havethese disadvantages. According to the invention, formulations aretherefore made available which have a controlled release profile whichresults in a high local active compound concentration at the site ofaction and simultaneously guarantees a blood level of the activecompound which is as low as possible.

[0018] In the context of the present invention, it has now been foundthat pellet formulations are particularly suitable for this purpose,since unlike a tablet they spread the pharmaceutical form reproduciblyover wide areas of the intestine and are thus particularly suitable fortreatment of inflammatory processes, which often affect relatively largesections of the intestinal tract. In order to achieve the necessarylocal active compound concentration, the active compound must in thiscase be released at the site of inflammation within a relatively shorttime (up to a few hours) without, however, it being released virtuallyimmediately, in order that its action does not wear off too rapidly.

[0019] The use of a swellable, gel-forming matrix such as described inFR-A 2 692 484 is not suitable for pellets having a diameter of ≦3 mm,since on account of the small diameter the polymer is very rapidlypenetrated by the water, eroded as a result, and the active compoundwould thus be released virtually immediately (about 30 min).

[0020] In the context of the present invention, however, it hassurprisingly been found that, if the active compound is present in thepellet core in a non gel-forming polymer matrix which is essentiallyinsoluble and permeable to intestinal fluids and the active compound, amarkedly reduced release of the active compound into the blood, withsimultaneously increased local concentration of the active compound atthe site of the disorder in the intestine, is guaranteed in comparisonwith aminosalicylic acid formulations already known in the prior art.

[0021] The present invention thus relates to an orally administrablepharmaceutical pellet formulation having a controlled release profilefor the treatment of the intestinal tract, which comprises a core and anenteric coating, and, if appropriate, further pharmaceutically tolerableadditives, the core including as a pharmaceutically active compoundaminosalicylic acid or a pharmaceutically tolerable salt or derivativethereof, wherein the active compound is present in the core in a nongel-forming polymer matrix which is essentially insoluble in theintestinal tract and permeable to intestinal fluids and the activecompound, the matrix-forming polymer making up at least 1% by weight ofthe total weight of the core.

[0022] The invention furthermore relates to a process for the productionof the pellets described above and their use for the production of amedicament for the treatment of intestinal disorders, such asinflammatory intestinal disorders, preferably in the active phase and/orin the remission phase, for the prevention of these disorders, for theprevention of the recurrrence of these disorders or secondary disordersresulting therefrom, and of possible accompanying disorders and also forthe treatment of intestinal cancer. The medicament is particularlysuitable for the treatment of inflammatory intestinal disorders such asCrohn's disease and ulcerative colitis, and for the prevention,treatment and/or prevention of the reformation of polyps in thegastrointestinal tract. Moreover, the medicament is suitable for theprevention of colorectal carcinomas in patients with adenomas and/orpolypous growth, in particular with polypous growth in the intestine.The medicament is moreover used for lowering the recurrence rate ofcolorectal polyps.

[0023] Preferred active compounds are 5-aminosalicylic acid (also calledmesalazine), 4-aminosalicylic acid and, serving as a prodrug for 5-ASA,2-hydroxy-5-phenylazobenzoic acid derivatives such as sulfasalazine(5-[4-(2-pyridylsulfamoyl)phenylazo]salicylic acid) and balsalazide (thesodium salt of the azo derivative of 4-aminobenzoyl-β-alanine and5-aminosalicylic acid). 5-ASA is particularly preferred.

[0024] In addition to the active compound, the pellet core comprises 1%by weight, based on the total weight of the core, of a matrix-forming,non gel-forming polymer which is essentially insoluble in the intestinaltract and permeable to intestinal fluids and the active compound.Suitable matrix-forming polymers are, for example, those polymers whichare known in the prior art as coating lacquers for delayed-releasepharmaceuticals, such as, for example, (meth)acrylic ester copolymers.

[0025] Among the polymers which are essentially insoluble in theintestinal tract and permeable to intestinal fluids and the activecompound, those are preferred which are insoluble or particularlypreferably water-insoluble in the intestinal tract.

[0026] Methyl acrylate copolymers and ammoniomethacrylate copolymers ofthe type such as can be obtained under the tradename Eudragit® RS/RL/NEare particularly preferred. As functional groups, these polymers haveester groups (Eudragit® NE) or ammonium groups (Eudragit® RL/RS).Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate,methyl methacrylate, trimethylammonioethyl methacrylate chloride) arepreferred. These polymers are obtainable, for example, as poly(ethylacrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion asEudragit® NE 40 D and as poly(ethyl acrylate, methyl methacrylate,trimethylammonioethyl methacrylate chloride) 1:2:0.1 in 12.5% strengthisopropanolic solution as Eudragit® RS 12.5 and in the composition1:2:0.2 as Eudragit® RL 12.5. The most preferred is Eudragit® NE 40 D.

[0027] The polymer must be present in an amount which is sufficient toform a matrix for the active compound and which guarantees a delayedrelease of the active compound. For this purpose, an amount of at least1% by weight, preferably at least 4% by weight, based on the totalweight of the core, has proven suitable. Larger amounts of, for example,approximately 21% by weight can also be employed. 4% by weight to 10% byweight is preferably employed.

[0028] The active compound is preferably homogeneously dispersed in thematrix described above and is released with a delay after dissolving theenteric coating. The matrix with the active compound homogeneouslydispersed therein advantageously extends through the entire core.

[0029] The enteric coating should only dissolve after the formulationhas left the stomach. Necessary coatings for this purpose are disclosedin the prior art (e.g. EP 0 453 001 A1).

[0030] Preferred enteric coatings according to the invention comprise amethacrylic acid copolymer or methylhydroxypropylcellulose phthalate.Poly(methacrylic acid, methyl methacrylates), which are obtainable underthe tradenames Eudragit® L or S and have free carboxyl groups asfunctional groups, are preferred. These polymers are insoluble in thegastric juice, but dissolve in digestive juices above pH 5.5-7 dependingon the number of functional carboxyl groups. Poly(methacrylic acid,methyl methacrylate) 1:1 (Eudragit® L 100; methacrylic acid copolymer,USP/NF type A) and poly(methacrylic acid, methyl methacrylate) 1:2(Eudragit® S; methacrylic acid copolymer, USP/NF type B) areparticularly preferred. Eudragit® L 100 is the most preferred. Mixturesof the coating materials mentioned, in particular of Eudragit® L andEudragit® S, can also be used.

[0031] The pellet formulation can comprise one or more coatings, howeverpellet formulations in which the pellet only comprises one coating arepreferred.

[0032] Both the core and the coating of the pellet formulation accordingto the invention can include one or more of the abovementioned matrix orcoating materials.

[0033] The pellet formulations according to the invention canadditionally contain further pharmaceutically tolerable additives bothin the core and in the coating. Examples of pharmaceutically tolerableadditives include polyvinylpyrrolidone, microcrystalline cellulose,silica, magnesium stearate, lactose, cornstarch, triethyl citrate, talc,titanium dioxide and polyethylene glycol.

[0034] A particularly preferred pellet formulation according to thepresent invention comprises 5-ASA as an active compound in the core in apoly(ethyl acrylate, methyl methacrylate) 2:1 matrix, the polymercontaining ester groups as functional groups, and an enteric coatingwhich contains poly(methacrylic acid, methyl methacrylate) 1:1 or 1:2with free carboxyl groups as functional groups, and, if appropriate,further pharmaceutically tolerable additives.

[0035] Moreover, a mixture of Eudragit® S and Eudragit® L, preferablyapproximately 1:1, is advantageously employed in a coating for thepellet formulations according to the invention.

[0036] The pellet formulation according to the invention isdistinguished by a controlled release profile. Preferably, the releaseof active compound in 0.1 M HCl after 2 h is <10%, in particular <5%,and in artificial gastric juice at pH 6.8 after 0.5 h 10-30%, inparticular 10-20%, after 2 h 40-60%, in particular 40-50%, and after 6 hat least 80%, in particular at least 85%.

[0037] The pellet formulations according to the invention can beprepared according to conventional processes known to the person skilledin the art. For example, the matrix material is first mixed with theactive compound and, if appropriate, the further pharmaceuticallytolerable additives and shaped to give pellets. The coating is thenapplied, e.g. sprayed on, in the form of a lacquer suspension in asuitable suspending agent such as ethanol and/or water. The pellets canin this case have a size of 0.1-3 mm, preferably 0.5-1 mm, and arecombined in unit dose forms such as tablets or capsules for theproduction of a medicament. The present invention therefore also relatesto pharmaceutical formulations which comprise the pellets according tothe invention, in particular gelatin capsules which contain the pelletsaccording to the invention.

[0038] On oral administration, the pellet formulations thus obtainedresult, in comparison with other preparations with the same activecompound, in lower active compound concentrations in the blood with asimultaneously higher concentration of the active compounds in theintestine, as a result of which the side effect potential caused by thesystemically available active compound or its metabolites, is markedlyreduced.

[0039] The pellet formulation according to the invention is thusparticularly suitable for the treatment of intestinal conditions inwhich a relatively long-term administration of the active compound isindicated, such as inflammatory intestinal disorders in their activephase and their remission phase, in the prevention of adenomas and/orpolyp formation, in the prevention of the recurrence of adenomas and/orpolyps and in the prevention of secondary disorders resulting therefromand possible accompanying disorders.

[0040]FIGS. 1 and 2 show graphs of the plasma concentrations of 5-ASA(FIG. 1) and Ac-5-ASA (FIG. 2) against time.

[0041] The following examples serve to illustrate the invention.

[0042] Example 1 describes two different pellet cores (Example 1.1-1.2)and four different pellet coatings (Example 1.a-1.d). The differentcores can be combined in any desired manner with the different coatings,the pellet core from Example 1.1 together with the coating from Example1.a being a particularly preferred example.

EXAMPLE 1

[0043] Examples of pellet cores:

[0044] 1.1 I Mesalazine 5000 g  II Cellulose, microcrystalline 1500 g III Hydroxypropylmethylcellulose 200 g IV Silica  25 g V Poly (ethylacrylate, methyl 750 g methacrylate) 2:1 as a 40% strength aqueousdispersion, tradename Eudragit ® NE 40 D VI Magnesium stearate 250 g

[0045] I-IV are mixed, moistened with V and intensively kneaded. VI isfinally scattered in. The moist mass is pressed through an extruder witha die bore of 1 mm. The extruded pellets are cut into pieces about 1 mmlong and rounded in a spheronizer. The pellets are dried at 60° C.

[0046] 1.2 I Mesalazine 5000 g II Cellulose, microcrystalline 1500 g IIIHydroxypropylmethylcellulose  200 g IV Silica  25 g V Poly (ethylacrylate, methyl 2500 g methacrylate, trimethylammonioethyl methacrylatechloride) 1:2:0.1; as a 12.5% strength isopropanolic solution; tradenameEudragit ® RS 12.5 VI Magnesium stearate  250 g

[0047] I-IV are mixed, moistened with V and intensively kneaded. VI isfinally scattered in. The moist mass is pressed through an extruder witha die bore of 1 mm. The extruded pellets are cut into pieces about 1 mmlong and rounded in a spheronizer. The pellets are dried at 60° C.

[0048] Examples of Pellet Coatings

[0049] Formulations for 5000 g pellets, corresponding to Examples1.1-1.2

[0050] 1.a I Poly (methacrylic acid, methyl 750 g methacrylate) 1:1;tradename Eudragit ® L 100; (methacrylic acid copolymer, USP/NF type A)II Triethyl citrate  75 g III Talc 200 g IV Titanium dioxide 125 g VMagnesium stearate  50 g

[0051] I is dissolved in 7000 g of an ethanol/water mixture (8:2). II-Vare suspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

[0052] 1.b I Poly (methacrylic acid, methyl 350 g methacrylate) 1:2;tradename Eudragit ® S; (methacrylic acid copolymer, USP/NF type B) IITriethyl citrate  35 g III Talc 100 g IV Titanium dioxide 125 g VMagnesium stearate  50 g

[0053] I is dissolved in 3500 g of an ethanol/water mixture (8:2). II-Vare suspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

[0054] 1.c I Poly (methacrylic acid, methyl 420 g methacrylate) 1:2;tradename Eudragit ® S; (methacrylic acid copolymer, USP/NF type B);poly (methacrylic acid, methyl methacrylate) 1:1; tradename Eudragit ® L100; (methacrylic acid copolymer, USP/NF type A) (mixed in the ratio1.1:1) II Triethyl citrate  75 g III Talc 200 g IV Titanium dioxide 125g V Magnesium stearate  50 g

[0055] I is dissolved in 5000 g of an ethanol/water mixture (8:2). II-Vare suspended in the solution; the lacquer suspension is sprayed on at afeed air temperature of 40° C. in a suitable apparatus.

[0056] 1.d I Methylhydroxypropylcellulose 410 g phthalate IIEthylcellulose  44 g III Polyethylene glycol 6000  40 g IV Talc 200 g VTitanium dioxide 125 g VI Magnesium stearate  50 g

[0057] I and II are dissolved in 5000 g of an ethanol/water mixture(9:1). III-VI are suspended in the solution; the lacquer suspension issprayed on at a feed air temperature of 40° C. in a suitable apparatus.

EXAMPLE 2

[0058] To determine the release of the active compound from the pelletsaccording to the invention, the “basket” method was used. The stirrerspeed was 100 rpm and the temperature was kept constant at 37° C. 0.1 MHCl according to USP was used as artificial gastric juice and USPphosphate buffer (pH 6.8) as artificial intestinal juice.

[0059] Table 1 indicates the active compound release of the pelletformulation according to the invention having a core according toExample 1.1 and a coating according to Example 1.a under theabove-mentioned conditions. TABLE 1 Release pH Time [min] [%] 1.2 1201.6 6.8  30 12.2  60 24.9  90 36.0 120 45.2 150 53.0 180 59.7 240 70.6300 78.8 360 85.4

EXAMPLE 3

[0060] In order to obtain results about the active compound absorptioninto the blood after administration of the pellet formulation accordingto the invention, the plasma concentrations of 5-ASA and acetyl-5-ASA(As-5-ASA), its degradation product, were investigated in atime-dependent manner. In a cross-over arrangement, 24 healthy subjectsreceived 500 mg of 5-ASA in two different pharmaceutical formulations(pellets according to the invention having a core according to Example1.1 and coating according to Example 1.a and commercially availableSalofalk® tablets (mesalazine in the form of enteric tablets) as acomparison preparation) over a period of 4 days (3×500 mg of 5-ASAdaily). To determine the plasma concentration of 5-ASA and acetyl-5-ASA,venous blood samples were taken from the subjects.

[0061] Tab. 2 shows the plasma concentration of 5-ASA and Ac-5-ASAaveraged from 24 patients under steady-state conditions. TABLE 2 Plasmaconcentration of 5-ASA and Ac-5-ASA in 24 subjects [ng/ml] (mean value)Time after Comparison adminis- Pellets preparation tration [h] [5-ASA][Ac-5-ASA] [5-ASA] [Ac-5-ASA] 0 63.49 676.35 198.42 1033.89 1 71.50739.46 96.66 711.70 2 102.97 731.34 82.86 657.16 3 382.02 1063.59 156.55675.83 4 686.03 1549.00 1293.30 1651.01 5 527.39 1653.73 1564.33 2511.996 456.70 1493.00 924.75 2243.11 7 384.25 1442.96 492.91 1755.05 8 257.161196.51 275.11 1377.46

[0062] It is evident from Table 2 and from FIGS. 1 and 2 that markedlylower plasma levels can be achieved both from 5-ASA and from itsmetabolite Ac-5-ASA if 5-ASA administered to the subjects in the form ofthe pellet formulation according to the invention. This result isconfirmed by the average C_(max) values (average of the C_(max) valuescalculated from the data of the individual subjects). In the case of thecomparison formulation, the average C_(max) value was 2001 ng/ml for5-ASA and 2617 ng/ml for Ac-5-ASA while in the case of the pelletformulation according to the invention the average C_(max) value was 755ng/ml for 5-ASA and 1810 ng/ml for Ac-5-ASA. The average C_(max) valueof the pellet formulation is thus only 37.7% of the average C_(max)value of the comparison formulation for 5-ASA and only 69% for Ac-5-ASA.

EXAMPLE 4

[0063] In order to confirm an increased local release of the 5-ASA inthe intestine, feces samples of 4 subjects who had received 1500 mg of5-ASA were investigated for 5-ASA and Ac-5-ASA in a furtherinvestigation. To this end, the feces of the subjects were collected for71 hours and investigated for free 5-ASA and Ac-5-ASA which were notbound in the pellet or in the comparison formulation (Tab. 3). Thepellets according to the invention employed were those having a coreaccording to Example 1.1 and a coating according to Example 1.a; thecomparison preparation used was commercially available Salofalk® tablets(mesalazine in the form of enteric tablets). TABLE 3 Cumulative fecalexcretion of 5-ASA and 5-Ac-ASA of 4 subjects [mg] (mean value) PelletsComparison preparation [5-ASA] [Ac-5-ASA] [5-ASA] [Ac-5-ASA] 287.5 367.9222.9 275.7

[0064] It is evident from the table that both the amount of the 5-ASAreleased in the intestine by the pellet formulation according to theinvention, at 287.5 mg, and the amount of free Ac-5-ASA, at 367.9 mg, ishigher by 29% or 44% respectively than in the comparison formulation.Since Ac-5-ASA can only be formed in the intestine by the interactionwith the intestinal mucous membrane, the increased amount of Ac-5-ASA inthe pellet formulation shows that markedly more active compound comesinto contact with the intestinal mucous membrane and can thus displayits curative action than in the comparison formulation.

[0065] These investigations confirm that the concentration of the activecompound 5-ASA or its degradation product Ac-5-ASA in the blood can besignificantly lowered by the pellet formulation according to theinvention in comparison with commercially available 5-ASA preparationsand thus the danger of possible side effects (nephrotoxicity etc.) isalso lower. As a result of the reduced absorption of the active compoundinto the blood, markedly higher amounts of the active compound areavailable in the intestine. These also come into contact with theintestinal mucous membrane and can display their action there, as theamounts of Ac-5-ASA, which are higher in comparison with the comparisonformulation and which are formed in the intestine by the direct contactof 5-ASA with the intestinal mucous membrane, confirm. Unlike thesystemically available 5-ASA and Ac-5-ASA, the 5-ASA and AC-5-ASApresent in the intestine cannot have a nephrotoxic action, since it isnot excreted via the kidney, but with the feces.

[0066] Thus the pellet formulation according to the invention ispreferably suitable for intestinal conditions in which a relativelylong-term administration of the active compound is indicated, such asinflammatory intestinal disorders in their active phase and in theirremission phase, in the prevention of polyp formation, in the preventionof the recurrence of polyps and in the prevention of secondary disordersresulting therefrom and possible accompanying disorders.

1. A process for preparing an orally administrable pharmaceutical pelletformulation having a controlled release profile for the treatment of theintestinal tract, which pellet comprises a core including anaminosalicyclic acid as a pharmaceutically active compound or apharmaceutically acceptable salt thereof and optionally pharmaceuticallytolerable additives, wherein the active compound is present in the corein a non gel-forming polymer matrix which matrix is essentiallyinsoluble in the intestinal tract and permeable to intestinal fluids andthe active compound, the matrix-forming polymer making up at least 1% byweight of the total weight of the core, the process comprising:extruding a moist mass of the matrix-forming polymer and the activecompound.
 2. The process of claim 1 wherein the matrix-forming polymeris co-poly(ethyl acrylate, methyl methacrylate) or ter-poly(ethylacrylate, methyl methacrylate, trimethylammonioethyl methacrylatechloride).
 3. The process of any of claims 1 to 2 wherein thematrix-forming polymer makes up 4 to 10% by weight of the total weightof the core.
 4. The process of any of claims 1 to 3 wherein theaminosalicyclic acid is 5-aminosalicyclic acid.
 5. The process of any ofclaims 1 to 4 wherein an enteric coating is applied to the pellet. 6.The process of claim 5 wherein the enteric coating comprises amethacrylic acid containing copolymer or methylhydroxypropyl cellulosephthalate.
 7. The process of claim 6 wherein the methacrylic acidcontaining copolymer is co-poly(methacrylic acid, methyl methacrylate),wherein the co-polymer contains free carboxylic acid functional groups.8. The process of any of claims 5 to 7 wherein a single coating layer isapplied to the pellet.